Adverse cutaneous reactions to chemotherapeutic drugs.

Drug reactions resulting from chemotherapy agents are common and frequently affect the skin. Although often benign, a select few of these cutaneous reactions may necessitate immediate changes to the antineoplastic regimens. Given the diversity of chemotherapeutic skin reactions and their complex implications on patient management, an organized conceptual schema is imperative for proper patient care. We evaluate a number of commonly seen chemotherapy-induced skin toxicities organized by pathogenic mechanism and drug class, providing a framework for the identification and categorization of adverse events to prevent unrecognition. Groupings of these reactions include direct cytotoxicity and/or drug accumulation, immunologic hypersensitivity, and aberrant molecular signaling.

Confusion in determination of two types of cutaneous adverse reactions to drugs, maculopapular eruption and erythema multiforme, among the experts: A proposal of standardized terminology.

The clinical classification of cutaneous adverse reactions by drugs should be clearly distinguished to avoid conceptual confusion and inconsistency. Although dermatologists appear to have established a roughly common consensus for cutaneous adverse reactions, some types are more rigorously defined than other, possibly misleading classifications. To assess the consensus on the clinical classifications, we investigated the concordance rate of diagnosis by Japanese experts through a snap visual inspection of various clinical pictures exhibiting erythema multiforme and maculopapular eruption types of cutaneous adverse reactions. The experts were shown images on a screen and were then asked to decide whether to classify cases as maculopapular eruption or erythema multiforme type, and the concordance rates were calculated. Overall, the mean concordance rate was 71.6% (standard deviation, 17.3%), and only 33.8% of cases had a 90% or more concordance rate. Our study shows that the determinations of erythema multiforme and maculopapular eruption types by the existing classification criteria were confusing even among experts, which prompted us to standardize the terminology. We propose clinically defining erythema multiforme type as generalized macules mainly of 1 cm or more with a tendency of elevation and coalescence, and maculopapular eruption type as generalized erythema other than erythema multiforme type. Currently, the clinical definitions of cutaneous adverse reactions are poorly described, which may be problematic upon analyzing large volumes of data. Our proposal for a new terminology will enhance the accuracy and consistency of information for the correct analysis of cutaneous adverse reactions.

Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management.

Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient's overall quality of life. This review will describe various cutaneous adverse events of anti-melanoma therapies and its management.

Severe cutaneous adverse drug reactions.

The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T-cell receptor (TCR): (i) the "hapten/prohapten" theory; (ii) the "p-i concept"; (iii) the "altered peptide repertoire"; and (iv) the "altered TCR repertoire". The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA-B*15:02 for carbamazepine-induced SJS/TEN and HLA-B*58:01 for allopurinol-induced SCAR), involvement of specific TCR, induction of T-cell-mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T-helper 1/2-associated cytokines) and cell death mechanism (e.g. miR-18a-5p-induced apoptosis; annexin A1 and formyl peptide receptor 1-induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin-induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved.

Reactive Granulomatous Dermatitis: A Review of Palisaded Neutrophilic and Granulomatous Dermatitis, Interstitial Granulomatous Dermatitis, Interstitial Granulomatous Drug Reaction, and a Proposed Reclassification.

The terms "palisaded neutrophilic and granulomatous dermatitis," "interstitial granulomatous dermatitis," and the subset "interstitial granulomatous drug reaction" are a source of confusion. There exists substantial overlap among the entities with few strict distinguishing features. We review the literature and highlight areas of distinction and overlap, and propose a streamlined diagnostic workup for patients presenting with this cutaneous reaction pattern. Because the systemic disease associations and requisite workup are similar, and the etiopathogenesis is poorly understood but likely similar among these entities, we propose the simplified unifying term "reactive granulomatous dermatitis" to encompass these entities.

Adverse cutaneous drug reactions--a clinico-demographic study in a tertiary care teaching hospital of the Kashmir Valley, India.

BACKGROUND: Adverse cutaneous drug reactions (ACDRs) are caused by a wide variety of agents. The aim was to study the incidence and clinico-demographic profile of ACDRs to identify any potential risk factors and compare the results with other studies. METHODS: A cross-sectional observational study was conducted over a period of one year from October 2012 to October 2013 in the outpatient department (OPD) of a tertiary care teaching hospital of the Kashmir valley in India and various ACDRs were recorded. RESULTS: The incidence of ACDRs was 0.16%. The mean age of patients was 39.36 ± 16.77 years. The male: female ratio was 0.97:1. The most frequently reported cutaneous reactions were with antimicrobials (57.33%) followed by NSAIDs (21.33%) and antiepileptic drugs (17.33%). Less common groups involved were steroids, antipsychotics and bisphosphonates (1.33% each). Fixed drug eruptions (FDEs) were the commonest (45.33%) followed by maculopapular (17.33%), photoallergic (8%), erythema multiforme (6.66%), Stevens-Johnson syndrome (5.33%) and lichenoid eruptions (4%). Less common patterns were urticaria, Drug Reaction with Eosinophilia and systemic symptoms (DRESS syndrome) and acneform eruptions (2.66% each) followed by angioedema, acute generalized exanthematous pustulosis (AGEP), exfoliative dermatitis and toxic epidermal necrolysis (1.33% each). CONCLUSION: Physicians should have adequate knowledge of adverse drug reactions, especially of newer drugs which are increasing every year in order to minimize such events.

[Delayed-type cutaneous drug reactions. Pathogenesis, clinical features and histology]. / Kutane Arzneimittelreaktionen vom Spättyp. Pathogenese, Klinik und Histologie.

BACKGROUND: Cutaneous reactions to drugs can be subdivided in different ways. In addition to the standard classification according to the etiopathogenesis there are also classifications based predominantly on morphological criteria. The majority of drug-related cutaneous adverse reactions are immunological reactions which are collectively classified under the term hypersensitivity. These reactions are based on drug-specific immunoglobulin E (IgE) or cell-mediated mechanisms, not on the mechanism of action of the drug and are unpredictable. Delayed type reactions to drugs are forms of type IV T-cell mediated hypersensitivity. A prerequisite is a stable association of a pharmaceutical substance with a protein so that hapten-protein conjugates can be produced. The most common clinical symptom is maculopapular (morbilliform) drug-related exanthema. This article also examines lichen planus like drug reaction and drug-induced (hematogenic) allergic contact dermatitis in more detail. DIAGNOSTICS: The diagnostics are never trivial but also include the differentiation from viral exanthema and initial phases of severe cutaneous adverse reactions, such as toxic epidermal necrolysis. In addition to the morphological classification, the final diagnosis encompasses the interpretation of histopathological alterations in the skin biopsy, analysis of patient medication history, laboratory results and inclusion of data from the literature. Patch tests can also have additional diagnostic benefits. In vitro tests which involve the cellular incubation of the drug responsible should be reserved for specialized laboratories. A prerequisite for successful treatment is immediate termination of the drug responsible. THERAPY AND PROGNOSIS: Therapy is symptomatic with topical and also short-term systemic steroids and antihistamines. The prognosis is very good.

Epidemiology of cutaneous drug-induced reactions.

Cutaneous reactions represent in many surveillance systems, the most frequent adverse events attributable to drugs. The spectrum of clinical manifestations is wide and virtually encompasses any known dermatological disease. The introduction of biological agents and so-called targeted therapies has further enlarged the number of reaction patterns especially linked with cytokine release or in balance. The frequency and clinical patterns of cutaneous reactions are influenced by drug use, prevalence of specific conditions (e.g., HIV infection) and pharmacogenetic traits of a population, and they may vary greatly among the different populations around the world. Studies of reaction rates in cohorts of hospitalized patients revealed incidence rates ranging from, 1 out 1000 to 2 out 100 of all hospitalized patients. For drugs such as aminopenicillines and sulfamides the incidence of skin reactions is in the order of 3-5 cases out of 100 exposed people. Although the majority of cutaneous reactions are mild and self-limiting, there are reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) which are associated with significant morbidity and mortality. Surveillance systems routed on sound epidemiologic methodology, are needed to raise signals and to assess risks associated with specific reactions and drug exposures. Identification of risk factors for adverse reactions and appropriate genetic screening of groups at higher risk may improve the outcomes of skin reactions.

[Cutaneous drug reactions imitating dermatoses]. / Dermatosen-imitierende kutane Arzneimittelreaktionen.

BACKGROUND: Cutaneous adverse drug reactions are frequent and present with heterogenous clinical manifestations. METHODS AND RESULTS: Increasingly, case reports describe drug reactions which mimic dermatoses, although exact data on prevalence are missing. Psoriasiform, lichenoid and pityriasiform exanthems are most frequent. The differentiation of these variants from the respective authentic dermatoses is difficult and only a few clinical and histological criteria are helpful. Other dermatoses like lupus erythematosus or bullous autoimmune dermatoses (pemphigus vulgaris, bullous pemphigoid) can be induced by drugs as well. These drug-triggered variations are classified as distinct subclasses of the respective dermatosis. CONCLUSIONS: Exact history and evaluation of the clinical course are essential for the diagnosis of drug reactions mimicking dermatoses and present an important challenge for the clinician. A clear-cut differentiation between the genuine dermatosis and its drug-driven simulator is not always possible.

Widespread morbilliform eruption associated with telaprevir: use of dermatologic consultation to increase tolerability.

IMPORTANCE: Telaprevir, combined with pegylated interferon alfa and ribavirin, is an efficacious approach to treat hepatitis C virus infection. A morbilliform eruption associated with telaprevir is a common adverse effect experienced by patients. Current guidelines mandate telaprevir discontinuation in any patient with a severe, progressive, or unresponsive cutaneous eruption. OBSERVATIONS: Eight patients with a grade 3 (severe) widespread morbilliform eruption associated with telaprevir were referred to dermatology for evaluation and treatment. Each patient received a combination of antihistamines, topical corticosteroids, and thick emollient creams, rendering their eruption tolerable for the duration of treatment. No patients had evidence of a systemic or life-threatening drug reaction, developed a systemic drug eruption, or had to prematurely stop triple therapy secondary to a cutaneous eruption. CONCLUSIONS AND RELEVANCE: Patients with an uncomplicated grade 3 (severe) widespread morbilliform eruption associated with telaprevir may be able to continue triple therapy with close monitoring and dermatologic consultation. Given our findings, we propose an additional clinical classification of the telaprevir-associated eruption to better reflect the dermatologic classification of drug eruptions.

[Rosacea: Clinical features and classification]. / Klinik und Klassifikation der Rosazea.

Rosacea is a frequent chronic dermatological disorder mainly affecting the face. Since it affects the appearance, it can be very distressing for the patient leading to psychosocial disturbances. Rosacea occurs in adults, peaking between 40 and 50 years of age. The course of rosacea is quite variable and the disease may stop at any stage. Generally, three main stages are differentiated: erythemato-teleangiectatic rosacea (rosacea stage I), papulopustular rosacea (rosacea stage II), hyperglandular-hypertrophic rosacea (rosacea stage III). Besides these main manifestations numerous special forms exist, which often lead to difficulties in the differential diagnoses and require specific therapeutic strategies. These include rosacea conglobata, rosacea fulminans, granulomatous rosacea, persisting edema, (Morbihan disease), gram negative rosacea, ocular rosacea, and steroid rosacea. Recently increasing numbers of patients have been observed, whose rosacea was were induced by inhibitors of epidermal growth factors (cetuximab, geftinib) used as chemotherapy in patients with different malignancies. These side effects have been described as acneiform eruptions but at least some of the described patients have a rosacea-like appearance; therefore, this form can be classified as a subset of drug induced rosacea.

[Cutaneous adverse reactions of EGFR (epidermal growth factor receptor)-inhibitors: therapeutic algorithm of the French PROCUR group]. / Toxicité cutanée des anti-EGFR (epidermal growth factor receptor) : algorithme thérapeutique du groupe français PROCUR.

The epidermal growth factor receptors (EGFR)-inhibitors are frequently responsible for cutaneous adverse drug reactions that may alter the patients' quality of life and hamper the continuation of treatment. We present here the experience of a group of French multidisciplinary experts - the PROCUR group (PRise en charge de la tOxicité CUtanée des anti-EGFR) - created in order to establish a therapeutic algorithm. It was built in three steps under the responsibility of a steering committee: (1) a systematic literature review was performed by a group of three dermatologists and one oncologist; (2) regional meetings evaluated practical aspect of the treatments in France; (3) a final meeting confrontating the practices in France and the evidence-based medicine including the steering committee, the bibliographic group, and oncologists, radiotherapists, dermatologists and hepato-gastroenterologists involved in regional scientific committees, resulted in a therapeutic algorithm, resulting in the collegial writing of this algorithm. This multidisciplinary study should facilitate the standardised, optimised management of skin toxicity associated with EGFR-inhibitors.

[The spectrum of drug eruptions]. / LeLa vignette diagnostique de l'etudiant. Le spectre des toxidermies.

Drug eruptions are frequently encountered and they represent "diseases of medical progress". They are expected in about 2% of treated patients. Their putative diagnosis is based on a set of imputability factors. Several distinct drug-induced skin disorders are identified. They are initially recognized from personal experience, but the implication to a specific drug derives from the collective experience of published evidence. Their histopathological aspect is often evocative or demonstrative for the nature of the dermatosis. Some drug eruptions follow an indolent course, while others are life-threatening.

Physiopathology of adverse cutaneous drug reactions--applied perceptions: part I.

Adverse cutaneous drug reactions are common, but their physiopathology is largely elusive. The authors assess various reactions to facilitate their diagnosis and treatment. Some of the common reaction patterns are included with the prime objective of highlighting their physiopathology.

[Undesired cutaneous adverse drug reactions: What is new?]. / Unerwünschte Arzneimittelreaktionen der Haut: Was gibt es Neues?

New therapeutic agents, i.e., biologicals, may induce a variety of novel cutaneous adverse reactions (CAR), which hardly can be assigned to existing classification systems. Basing on clinical examples, we present a recently established classification system for CAR to novel drugs. In addition, management strategies for CAR to tumor necrosis factor-α antagonists and to epidermal growth factor receptor inhibitors are discussed.

Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions: the randomized EVEREST study.

PURPOSE: Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. PATIENTS AND METHODS: After 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). RESULTS: The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. CONCLUSION: Cetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.

A new proposal for a clinical-oriented subclassification of baboon syndrome and a review of baboon syndrome.

OBJECTIVE: To review baboon syndrome (BS). DATA SOURCES: Date sources were obtained from PubMed and Google Scholar: Photographs of baboon syndrome were obtained from our patient. STUDY SELECTIONS: PubMed and Google Scholar were searched up to June 30, 2010. The search terms were "baboon syndrome", "SDRIFE" and "thimerosal allergy". Reverse references from relevant articles and Google Scholar were also used. As BS is a classical disease and cases of offending agents were relatively old, some references were more than five years old. In order to gather as many cases of offending agents as possible, more than 50 references were collected. RESULTS AND CONCLUSION: We divided BS into as 4 groups; classical baboon syndrome, topical drug-induced baboon syndrome, systemic drug-induced baboon syndrome and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). The pathomechanism of BS is still unknown. A delayed type of hypersensitivity reaction, a recall phenomenon, pharmacologic interaction with immune-receptors and anatomical factors may be involved in the causation of BS.